2-4-halobenzyl phenols and preparation thereof

ABSTRACT

The specification describes novel 2-(4&#39;&#39;-halobenzyl) phenols of the formula:   IN WHICH R1, R2 and R3, which may be the same or different, are hydrogen or a lower alkyl group, provided that only one of R1, R2 and R3 is hydrogen, or any two or R1, R2 and R3 form, together with the carbon atom to which they are attached, a cycloalkyl ring, particularly cyclohexyl, and the third substituent is hydrogen; R4 is hydrogen, halogen, a nitro group or a benzyl group, the latter, if desired, being substituted in the same manner as the benzyl group shown in the ortho position of the phenolic nucleus; R5 is hydrogen or a hydroxyl group; X is halogen, particularly chlorine or bromine, and Y is hydrogen or halogen, particularly chlorine or bromine, and a process for their preparation. These compounds have useful bacteriostatic activity.

llnited States Patent [1 1 Debat 2-4-HALOBENZYL PHENOLS AND PREPARATIONTHEREOF [75] Inventor: Jacques Debat, Paris, France [73] Assignee:Societe a Responsabilite Limitee dite: Institut de Recherches Chimiqueset BiologiquesAppliquees (I.R.C.E.B.A.), Paris, France [22'] Filed: June28, 1972 [21] Appl. No.: 267,073

Related US. Application Data [63] Continuation of Ser. No. 755,232, Aug.26, 1968,

abandoned.

[30] Foreign Application Priority Data Aug, 31, 1967 Great Britain39816/67 [52] US. Cl 260/619 R, 260/619 D, 424/347 [51] Int. Cl. C07c39/12, C07c 39/24 [58] Field of Search.. 260/619 R, 619 A [56]References Cited 7 UNITED STATES PATENTS 1,967,825 7/1934 Klarmann eta1. 260/619 A X 1,926,874 9/1933 Klarmann et a1. 260/619 A X 1,926,8739/1933 Klarmann et al. 260/619 A X Attorney, Agent, or Firm-Bacon &Thomas [451 Dec. 17, 1974 ['57] ABSTRACT The specification describesnovel -2-(4-halobenzyl) phenols of the formula:

in which R,, R and R which may be the same or different, are hydrogenor'a lower alkyl group, provided that only one of R,, R and R ishydrogen, or any two or R R and R form, together with the carbon atom towhich they are attached, a cycloalkyl ring, particularly cyclohexyl, andthe third substituent is hydrogen;

R is hydrogen, halogen a nitro group or a benzyl group, the latter, ifdesired, being substituted in the FREQUENCY (04%) 3000 2500' 200018001600 PATENTED DEC 1 71974 SHEET 03UF i4 (PHCQONS) WAVELENGTH (.LNBDHEId)avNviuwswval a l J INVENTOR B JACQUES DEBAT ATTO mms PJJEHTED HEB 1T1974 3 855 317 sum 09 0F 14 INVENTOR JACQUES DE BAT 15W x M amzouuiv1523."; 2

ATTORNEYS m 3 m. 9 m m n w m N3 fi ls m N g 1 mm w .6 l u 3 V N w? w wom 3 N P 7 h 1 1 9% 2R SR 00% Rm 8m Rm 82 com. 83 gm 3m: 83 3% 26m 8%80m 82: 9.21 675333 2,4-HALOBENZYL PHENOLS AND PREPARATION THEREOF 6 illin which R,, R and R which may be the same or different, are hydrogen ora lower alkyl group, provided that only one of R R and R is hydrogen, orany two of R R and R form, together with the carbon atom to which theyare attached, a cycloalkyl ring, particularly cyclohexyl, and the thirdsubstituent is hydrogen; R is hydrogen, halogen, a nitro group or abenzyl group, the latter, if desired, being substituted in the samemanner as the-benzyl group shown in the ortho position of the phenolicnucleus;.R is hydrogen or a hydroxyl group; X is halogen, particularlychlorine or bromine, and Y is hydrogen or halogen, particularly chlorineor bromine, have valuable pharmacological properties. In particular theyare effective bacteriostatic agents having high activity accompanied byrelatively low toxicity.

Phenol and its derivative substituted with a methyl group,'the cresols,have been used as bacteriostatic agents but they have low bacteriostaticactivity. The following inhibiting dilutions were found effective in theconditions, described hereinafter, under which the compoundsor Formula Iwere tested:

Phenol: moon I Para-cresol: 1/4000 Moreover, these compoundsv are highlytoxic and can only be used externally.

A detailed study of the cresols, their analogues and compounds ofsimilar structure was carried out and it was found that benzyl phenolsare more active than cresols with respect to Gram-positive bacteria. Itwas also fund that benzyl; cresols in which the methyl group is replacedby a heavier hydrocarbon chain are more active than non-substitutedbenzyl phenols and a series of benzyl phenol substitution homologuescontaining straight, branched or cyclic hydrocarbon groups para to thephenol group was accordingly prepared. On testing their activity andtoxicity, it was surprisingly found that the benzyl phenols substitutedwith branched or cyclic hydrocarbon groups were considerably more activethan the corresponding straight chain homologues and known analogouscompounds. Furthermore, the increase in activity is accompanied by adistinct decrease in toxicity-in comparison with the compounds of theother series.

The compounds having the above-described advantages are the compounds ofFormula 1; these compounds are novel and constitute one aspect of thepresent invention.

The compounds of Formula I can be prepared by a process which comprisesreacting a phenol of the formula: I I OH a d. R ha e t e a d meanings,with a substituted benzyl chloride of the formula:

in which X and Y have the above-stated meanings, in the presence of zincchloride .and preferably in the presence of a solvent, such aschloroforme, at the reflux temperature of the solvent, an excess of thephenol with repsect to the substituted benzyl chloride being used whenR, in the desired product is not a substituted benzyl group identical tothe substituted benzyl group in the ortho-position of the phenolic ringand an excess of the substituted benzyl chloride with respect to thephenol being used when R, in the desired product is a substituted benzylgroup identical to the orthosubstitutent in the phenolic ring. In orderto prepare the nitro compounds (compounds of Formula I in which R., isN0 the compounds prepared by this process (using an excess of phenol)are nitrated with nitric acid in glacial acetic acid. v

For use in human and veterinary medicine, the compounds of Formula I aregenerally mixed with an inert physiologically acceptable carriersuitable for the intended mode of administration, most of the compoundscan be administered orally for the treatment of infectious diseases; thenitro derivatives (compounds of F ormula I in which R, is N0 are,however, more suitable for external application.

In order that the invention may be more fully understood, the followingExamples are given by way of illustration only. In these Examples, thefollowing general method of preparation was used. Quantitiesproportional to one mole of phenol and 0.75 mole of monohalobenzylchloride or dihalobenzyl chloride are dissolved in 750 ml of anhydrouschloroform, 0.06 mole of crushed fused zinc chlorideis then added andthe resulting mixture is gently refluxed for between and 24 hours. Aftercooling, 750 ml of water are added to the reaction mixture, which isthen stirred and the organic phase decanted off. The organic phase iswashed with water until it reaches a pH of 7 and is then dried on sodiumsulphate. The solvent is evaporated and the residue is distilled underreduced pressure.

EXAMPLE 1 2-(4'-chlorobenzyl)-4-sec-butylphenol The following were usedas reagents in the general method described above:

g of p-chlorobenzyl chloride g of 4-secondary butylphenol 18 g of fusedzinc chloride 200 ml of dry chloroform The reaction mixture was heatedin two periods for a total of 21 hours; liberation of HCl stopped afterabout 19 hours. 200 ml of cold distilled water were added to the cooledreaction mixture and, after stirring, the organic phase was decantedoff. The aqueous phase was extracted twice with 20 ml of chloroform andthe chloroformic liquors were combined and washed four times with 25 mlof distilled water. The chloroform solution was dried with 75 g ofanhydrous sodium sulphate and, after filtering, a clear solution wasobtained. The solvent was evaporated off, first at normal pressure andthen under reduced pressure (A mm Hg), and the residue was distilled. Afirst fraction distilled over at between 85 and 115C and consisted ofunreacted starting material. A second fraction distilled over at between160C and 178C and consisted of the desired product in a practically purestate. This fraction was recrystallised by dissolving it in 60 ml ofboiling petroleum ether and then cooling to lC. The resulting product,having an empirical formula G i-1 0C] (molecular weight 274.5), meltedat 57C (measured with a Maquenne block).

EXAMPLES 2 to 11 The same general method as described in Example 1 wasused in the preparation of the compounds of these Examples, which areidentified by their chemical name, empirical formula, molecular weightand one or more of the following constants: melting point (m.p.)measured with a Maquenne block, boiling point (b.p.) at specifiedpressure in mm Hg, and the refractive index EXAMPLE 22-(4'-chlorobenzyl)-4-isopropylphenol m.p. 57C

EXAMPLE 3 2-(4'-chlorobenzyl)-4-t-butylphenol C H OCl 274.5

m.p. 86C

EXAMPLE 4 2-(2,4'-dichlorobenzyl)-4-isopropylphenol CmHmOClg b.p. 0.2182C EXAMPLE 5 2 (2',4'-dichlorobenzyl)-4-t-butylphenol EXAMPLE 62-(2',4'-dichlorobenzyl)-4-s-butylphenol CnHmOClg hp. 0.3 170C 11""1.5796

EXAMPLE 7 2-( 3 ',4'-dich1orobenzyl)-4-t-butylpheno1 EXAMPLE 82-(3',4-dichlorobenzyl)-4-s-butylphenol C H oCl- 309 5 b.p. 0.2 160-l62CEXAMPLE 9 l0 2-(3,4'-dichlorobenzyl)-6-chloro-4-t-butylphenol cnH oclahp 0.3 172174C n- 1.5835

EXAMPLE l0 2-(2',4'-dichlorobenzyl)-6-chloro-4-t-butylphenol C I-1 0C]343.5 b.p. 0.2 153-156C n 1.5823

EXAMPLE 11 2-(3,4'-dichlorobonzyl)4-isopropylphenol c aHmoclg b.p. 0.4l80-l85C EXAMPLES l2 and 13 The following method was used to preparecertain compounds of Formula 1 in which R is N0 150 ml of glacial aceticacid and 8 g of nitric acid (d 1.49) were placed in a three-necked flaskhaving a capacity of 500 ml. The flask was cooled externally by a coldwater bath and was equipped with a reflux condenser and a brominefunnel; it was also provided with a thermometer and an internal magneticstirrer.

A solution of 17 g of the compound of Example 5 or 7 in 50 ml of glacialacetic acid was added through the bromine funnel over a period of 20minutes. The temperature of the water bath was then raised'over a periodof 30 minutes to 70C and this temperature was maintained for 15 minutes,after which the mixture was left to cool and then poured into 1000 ml ofwater. The resulting mixture was thoroughly stirred and the oil phasedecanted off. crystallisation in the oil phase was induced by agitationor, if possible, by seeding with a sample of a previous operation.

The resulting crystals were dried, washed with plenty of water and thenrecrystallised from ethanol; the yield of recrystallised product was60%.

The following compounds were prepared by the above-described method:

EXAMPLE 12 2-(3',4'-dichlorobenzyl)-6-nitro-4-t-butylphenol (prepared bynitrating the compound in Example 7) CnHnOaNClg m.p. 106C EXAMPLE 132-(2',4'-dichlorobenzyl)-6-nitro-4-t-butylphenol EXAMPLES 14 to 18formula were prepared:

in which R,, R R and Y have the above-stated-meanmgs. EXAMPLE 14,

2,6-Di(4'-ch1orobenzyl)-4-isopropylphenol c n ocl 385 m.p. 93C

EXAMPLE l5 2,6-Di-(4'-chlorobenzyl)-4-s-butylphenol C H OCI 399 m.p. 93C5 EXAMPLE l6 2,6-Di-(2',4'-dichlorobenzyl)-4isopr0pylphen0l C H OCI; 454b.p. 1 250C EXAMPLE 17 2,6-Di-(2,4'-dich1orobenzyl)-4#t-butylpheno1 C HOCL 468 b.p. 0.2 238240C EXAMPLE l8 2,6-Di-(3';4-dichlorobenzyl)-4-tbutylphenol CgqHggOCL; b.p. 0.2 238240C n approx. 1.605

EXAMPLES 19.10 21 In these Examples, benzyl phenols of Formula Icontaining 21 cyclohexyl radical inthe para position-of the phenol groupwere prepared by the method of Example 5 1.

. EXAMPLE 19 2-(4'-ch1orobenzy1)-4-cyc1ohexy1pheno1 c gHz ocl m.p. 105Cv EXAMPLE 20 2-( 3 ',4'-dich1or0benzy1)-4-cyc10hexy1pheno1 EXAMPLE 212-(3 ,4'-dich1orobenzy1)-4-cyclohexyl-6-ch1orophenol EXAMPLES 22 to 24The bromobenzyl phenols of these Examples were prepared by the methodofExample 1 using the para- 5 bromobenzyl chlorides instead of thechloro-analogue.

They have the general formula in which R R R R and have theabove-statedEXAMPLE 24 2-(4-bromobenzyl)-4-s-butylphenol m.p. 59C

EXAMPLES 25 to 30 The compounds of these Examples were prepared tocompare pharma'cologically with the branched-chain v compounds ofFormula 1.

EXAMPLE 25 2-( 4'-chlorobenzy1)-4-methylpheno1 C H OC1= 232.5 b.p. 12207C n 1.5968

EXAMPLE 26 2-(3',4'-dichlorobenzyl)-4-methylphenol C M- 001.- 267 b.p.20 240C 0 mp. 78C

EXAMPLE 27 2-(2,4-dichlorobenzyl-4-methylphenol b.p. 13 221C n 1.6100

EXAMPLE 28 2-(.3,4' -dichlorobenzyl)-4-n.hexylphenol C H OCl b.p. 0.1221224C n 1.5516

EXAMPLE 29 2-(4'-ch1orobenzy1)-4-n.hexylphenol 0. 11 00 302.5

b.p. 0.1 215-21sc n 1.5434

EXAMPLE 30 2-(2',4'-dichlorobenzyl)-4-n.hexylphenol C H OCl b.p. 0.2230235C n 1.5491

EXAMPLES 31 to 34 The compounds of these Examples are benzyl resorcinolssubstituted with a n-hexyl group para to the OH group of the resorcinolwhich is adjacent the benzyl group and were also prepared for thepurposes of comparison.

EXAMPLE 31 2-( 4-chlorobenzyl )-4-n.hexyl-resorcinol EXAMPLE 32'4'-dichlorobenzyl )-4-n.hexy1-resorcin 1s 22 2 2 353 b.p. 1.5 235238C1.5782

EXAMPLE 33 2-( 2 ,4 -dichlorobenzyl )-4-n.hexyl-resorcin0l EXAMPLE 352-(4'-chlorobenzy1)-4-methoxyphenol l-l 13 2Cl 248.5 FIGS. 1 to 14 ofthe accompanying drawings show the infra-red spectra of certain of thecompounds of the Examples. as follows:

Figure oouotnht-nu- Continued Figure Example The spectra were recordedwith a Perkin Elmer instrument using KCl pellets or thinly sliced filmsbetween two NaCl windows. The abscissae of the curves of the Figuresshowthe wavelength in microns or the frequencies in em while the ordinatesshow the percentage transmittance.

The compounds of Formula 1 were also studied toxicologically andpharmacologically.

The acute toxicity'per 05 was determined in mice by the followingmethod. Different doses of each compound were each tested on 10 mice,both male and female, weighing on average from 18 to 22 g; each dose wasadministered as a suspension in 10% gum arabic or olive oil and eachmouse was given a uniform dose of 0.4 ml per 20 g weight of mouse withthe aid of a probang.

The mice were starved for two hours before the experiment and thetemperature and behaviour of the animals were observed before the testand 1 /2 and 3 hours after ingestion of the compound. After this timethey were replaced in their cages and observed for several clays.

The number of dead was counted daily and from this was deduced thelethal dose 50 (LD 50), the maximum .tolerated dose '(MTD) and theminimum mortal dose MMD). The results are shown in Table 1.

The results of Table 1 show that the toxicity (LD50) of the compounds ofthe invention is always equal to and often higher than 1.5 g/kg, andsometimes higher than 2.5 g/kg. Y

The bacteriostatic activities in vitro of the compounds of Formula 1were determined by comparing them with known products, particularly ofanalogous series. The activity was determined with respect to thespecific Gram-positive London staphylococcus as a reference strain forall the compounds.

The test was carried out in a culture both of the following formula:

lndole-free bacteriolo 'cal ptone 40% b wei t edium chloride g] pc 5% byweiglit ucose The method used involved'progressive dilution of theprinciple tested. The dilutions varied by thousandths betweenconcentrations of one thousandth and one tenth of a thousandth, and bythousandths for concentrations between one tenth of a thousandth and1/100 of a thousandth, and by hundred thousandths for concentrationsbetween 1/100 of a thousandth and one millionth. If the, product wasfound active at a dilution of l millionth, a new range was made frommillionth to millionth to beyond 1 millionth.

Two dilution series were made independently and the results of the twoseries must be identical. The readings were carried out after 24 hours.

While the activity of formol or cresol is between 1/1 ,000 and 1/l0,000according to the strain, the compounds of Formula I have an activity ofat least l/30,000 on Gram-positive bacteria. Several of these substancesare active at 1/600,000, I 1/800,000, l/l,O00,0()0, and even beyond.

Table ll indicates the increase in activity resulting from differentsubstituents. It will be seen in particular that the alkyl substituentscontaining 3, 4, or more carbon atoms have greater activity than methylphenols, i.e. derivatives of para-cresol.

Number of Example showing compound used.

The figure given in the table is thatof the maximum dilution at whichthe growth of London staphylococcus is inhibited.

Activity at a dilution of l/l,000,000- for the compound of Example 10and 1/300,000 for the compound of Example 9 was also observed.

The activities of the series of symmetrical dibenzylphenols of Formula(I) are given in Table "I.

The activities of the bromo derivatives of Formula'l are given in TableIV.

TABLE IV Compound of Example Activity with respect to v No.Gram-positive London staphylococcus 22 /300.000 23 l/200,()00 24l/500.000

By comparison with the corresponding chloro derivatives of Examples 1, 2and 3, which have activities of l/600,000, l/600,000 and l/800,000,respectively, it can be seen that the replacement of chlorine by brominecauses a lowering of activity with respect to Gram-positive bacteria.

Iclaim:

l. The compound 2-(2', 4'-dichlorobenzyl)-4 ter. butylphenol. g '2. Thecompound 2-(2' ,4'-dichlorobenzyl)-4-sec. butylphenol.

3. The compound 2-(3',4'-dichlorobenzyl)-4-sec. butylphenol.

4. The compound 2-(3',4-dichlorobenzyl)-4- isopropylphenol.

1. THE COMPOUND 2-(2'', 4''-DICHLOROBENZYL)-4-TER. BUTYLPHENOL.
 2. Thecompound 2-(2'',4''-dichlorobenzyl)-4-sec. butylphenol.
 3. The compound2-(3'',4''-dichlorobenzyl)-4-sec. butylphenol.
 4. The compound2-(3'',4''-dichlorobenzyl)-4-isopropylphenol.